The important role of lactoferrin in innate mucosal immunity is well described. Neutrophils, which are the most abundant and rapidly mobilized immune cell within the circulation, constitute along with glandular epithelial cells the sole source of lactoferrin in vivo. Neutrophils, however, also are well recognized as pro-inflammatory cells, due in part to the release of proteases such as elastase and matrix metalloproteinase-9 (MMP-9). Neutrophils also are directly implicated in the pathogenesis of various mucosal-related diseases, including inflammatory bowel disease, gastritis, cystic fibrosis, and periodontal disease. Although lactoferrin is a distinguishing component of neutrophil secondary granules, results obtained by the Principal Investigator demonstrate that lactoferrin is also constitutively present on the surface of resting neutrophils. In addition, results suggest that neutrophil activation by chemoattractants induces a conformational change in the surface-associated lactoferrin. These observations, together with the demonstrated lactoferrin- binding activity of several bacterial pathogens associated with mucosal infection, suggest that the surface-associated lactoferrin may either directly mediate neutrophil activation or may contribute to the regulation of neutrophil function by lactoferrin-binding organisms. As such, lactoferrin- mediated activation and resultant degranulation of the neutrophils would amplify the mucosal host defense response but, at the same time, also trigger mucosal damage and potentially lead to inflammatory pathogenesis. Alternatively, lactoferrin-mediated induction of neutrophil apoptosis could provide a survival benefit to lactoferrin binding organisms by limiting neutrophil activation and subsequent release of the various host defense mediators. Accordingly, this proposal has two specific aims. (1) Does surface-associated lactoferrin mediate neutrophil activation and/or regulate neutrophil function?; (2) Does neutrophil activation by chemoattractants alter the capacity of surface-associated lactoferrin to mediate or regulate neutrophil function? It is proposed that the results of this study will identify a new mechanism for the activation or regulation of neutrophil function with direct implications for mucosal immunity and pathogenesis.